Adhesion molecule expression dictates the type of inflammatory response initiated, therefore the development of therapeutics designed at inhibiting adhesion molecule function seem very worthwhile. However, our preliminary data indicates that selective adhesion molecule inhibition may amplify certain inflammatory responses. Thus, compensatory adhesion molecule expression may be functioning in this in vivo environment and may work in a similar fashion as cytokine networks. For example, it is well established that IL-13 has many properties similar to IL-4. Likewise, IL-15 has redundant properties to IL-2, and IL-1beta has similar properties to IL-18. It may be that as the immune system became more sophisticated, there evolved built in backup mechanisms, attenuating the overall importance of any 1 cytokine. Therefore, as observed with cytokine networks, certain adhesion molecules may compensate for missing or antagonized ones. Overall, this proposal will provide novel insight pertaining to the initiation and maintenance of inflammation by linking adhesion molecule expression, monokine regulation, and leukocyte recruitment. These studies will demonstrate the complexity involved in targeting adhesion molecules as a potential therapeutic strategy for the treatment of RA and other inflammatory disorders. While common dogma suggests IL-1beta regulates selectins, this study proposes the novel hypothesis that in vivo E- and P-selectins regulate IL-1beta production and CIA development. [unreadable] [unreadable] [unreadable]